4,6-DICHLORO-3-PYRIDINEMETHANOL

Ethyl 4, 6-dichloronicotinate (12.5 g, 56.81 mmol) was dissolved in 500 mL of absolute ethanol and then sodium borohydride (6.45 g, 170.4 Mmol) and lithium bromide (7.4 g, 85.2 mmol) were added and stirred at room temperature for 5 h. The reaction solution was concentrated under reduced pressure, water was added, and the mixture was extracted with ethyl acetate and separated The organic phase was dried and the organic phase was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 3: 1) Color of solid (4, 6-dichloropyridin-3-yl) methanol (8.1 g, yield 80.1percent).Ethyl 4, 6-dichloronicotinate (12.5 g, 56.81 mmol) was dissolved in 500 mL of absolute ethanol and then sodium borohydride(6.45 g, 170.4 mmol) and lithium bromide (7.4 g, 85.2 mmol) were added and stirred at room temperature for 5 h. The reaction mixture was concentrated under reduced pressure, extracted with water, extracted with ethyl acetate. The organic phase was separated and dried. The organic phase was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 3: 1) To give (4, 6-dichloropyridin-3-yl) methanol as a white solid (8.1 g, yield 80.1percent).A)To a stirred solution of ethyl 4, 6-dichloronicotinate (8.8 g, 40 mmol) in ~ anhydrous THF (75 mL) cooled in an ice-water bath was added in a dropwise fashion 1 M LiAlHExample IX [01366] To a 5000-mL 4-necked round-bottom flask purged and maintained with an inert atmosphere of nitrogen was placed 4, 6-dichloropyridine-3-carboxylic acid (95 g, 494.79 mmol, 1.00 equiv) and tetrahydrofuran (1000 mL) followed by the addition of BH3.THF (1 M) (2111 mL, 4.20 equiv) dropwise with stirring at 0°C. The reaction mixture was stirred at 0°C for 30 mm and at room temperature overnight, quenched by the addition of 1000 mL of water/ice, and extracted with 3x1000 mL of ethyl acetate. The combined organic layers were dried over anhydrous sodium sulfate and concentrated under vacuum to afford 78.4 g (89percent) of (4, 6-dichloropyridin-3-yl)methanol as a white solid.To a 5000-mL 4-necked round-bottom flask, purged and maintained with an inert atmosphere of nitrogen, was placed 4, 6-dichloropyridine-3-carboxylic acid (95 g, 494.79 mmol, 1.00 equiv) and tetrahydrofuran (1000 mL), followed by the addition of BHPart I-- Synthesis of (4, 6-dichloropyridin-3-yl)methanol [0230] Methyl 4, 6-dichloronicotinate (5 g, 24 mmol) was dissolved in THF (140 mL) to form a solution. Next, solid sodium borohydride (4.6 g, 120 mmol) was added to the solution, followed by dropwise addition of MeOH (140 mL) over five minutes. After 2 hours, saturated NH(4, 6-Dichloro-pyridin-3-yl)-methanol:; To lithium aluminum hydride (2.4 g, 64 mmol) and aluminum chloride (17 g, 128 mmol) in EtTo a solution of methyl 4, 6-dichloropyridine-3-carboxylate (1 g, 4.854 mmol) in anhydrous THF (25 mL) was added a 1 M solution of diisobutylaluminium hydride in toluene (14.5 mL, 14.5 mmol) dropwise under nitrogen atmosphere at -78 °C. The reaction mixture was stirred for 2h during which reaction mixture slowly warmed to 0 °C. The progress of reaction was monitored by TLC. After completion of reaction, the mixture was quenched with saturated ammonium chloride solution (20 mL). EtOAc (100 mL) was added to the reaction mixture which was filtered. The filtrate was washed with water (30 mL) followed by brine wash (30 mL). The organic layer was separated, dried over anhydrous sodium sulfate and concentrated under reduced pressure to afford (4, 6-dichloro-3-pyridyl)methanol (820 mg) as a white solid.To a stirred solution of ethyl 4, 6-dichloronicotinate (36.8 g, 1.0 eq) in DCM (250 mL) at -78°C under nitrogen atmosphere, DiBAL-H (1.2 eq, 1M solution in toluene) was added drop wise and stirred at -78°C for 30 min while monitoring by TLC. After TLC showed completion of starting material, the solution was quenched with saturated ammonium chloride solution (50 mL) at -78°C and diluted with DCM (1 L). The layers were separated and the organic layer was washed with brine (200 mL), dried over anhydrous sodium sulphate, filtered and concentrated. The resulting crude material was purified by flash chromatography (Combiflash® - Redisep, 120 g) using EtOAc in hexane as the eluent. The 4, 6-dichloronicotinaldehyde was eluted at 7percent EtOAc in hexane and the (4, 6-dichloropyridin-3-yl)methanol was eluted at 10percent EtOAc in hexane. The aldehyde fractions were concentrated to obtain aldehyde as white solid (9.86 g, 33.5percent). 1H NMR (400 MHz, CDC1

Molecular Weight:178.01
XLogP3:1.6
Hydrogen Bond Donor Count:1
Hydrogen Bond Acceptor Count:2
Rotatable Bond Count:1
Exact Mass:176.9748192
Monoisotopic Mass:176.9748192
Topological Polar Surface Area:33.1
Heavy Atom Count:10
Complexity:112
Covalently-Bonded Unit Count:1
Compound Is Canonicalized:Yes